Marijuana (MJ) use continues to be the most popular illicit drug used among adolescents (1). In adults, MJ use is associated with poor inhibitory control and affective processing (41-52). The neural correlates of these processes are primarily in frontolimbic regions (53, 55, 58, 63, 67, 114), which continue to develop into adolescence (71- 82, 85-87). Frontolimbic functioning in adolescent MJ users has only begun to be characterized; chronic use of MJ is associated with poor executive functioning (111-116), aberrant prefrontal cortex and amygdala brain structure in females (112,118,121,203) and abnormal brain response to an inhibitory control task (114). Despite evidence of poor mood (112), it is unknown whether adolescent MJ use impacts brain function during affective processing. Currently, there are no known treatments to ameliorate aberrant frontolimbic brain functioning in adolescents. Both physical activity and cardiorespiratory fitness have been shown to have positive effects on brain function in adults (143,155-164). Although the findings in younger samples are promising (169-179), few studies have examined whether physical activity or cardiorespiratory fitness affect neurocognitive functioning in healthy adolescents. Further, it is unknown whether extent of physical activity or fitness moderates the negative consequences of chronic MJ exposure on frontolimbic brain functioning in adolescents. Our primary aims are to 1) characterize the effects of MJ use on frontolimbic brain functioning and connectivity and 2) determine whether extent of physical activity or cardiorespiratory fitness moderate these effects in adolescent normal controls (n=50) and heavy MJ users (n=50). Both groups will be balanced for 50 percent highly active and 50 percent sedentary individuals. Body mass index, ethnicity and gender will be balanced across groups. Teens will undergo a three week monitored abstinence period during which continuous activity data (by accelerometer and diary) will be collected. They will then have VO2 maximum testing to establish extent of cardiorespiratory (aerobic) fitness. Finally, teens will be administered a psychological and neuropsychological battery (measuring physical activity, nutrition, substance use, mood, personality, coping styles, and cognitive functioning) and undergo structural and functional magnetic resonance imaging (fMRI). Specifically, teens will complete inhibitory control and affective processing fMRI tasks. The direct and indirect relationships between MJ use, physical activity and fitness, and frontolimbic functioning and connectivity during the fMRI tasks will be examined. Brain structure and behavioral correlates of frontolimbic functioning will also be examined. Thus, the proposal will provide a better understanding of consequences of MJ use on frontolimbic functioning in adolescents and will determine whether increased physical activity or fitness normalizes these negative effects. This will lead to the design of low-cost ameliorative tools in reducing negative consequences of repeated MJ use in teens. Ultimately, results will help improve prevention strategies and behavioral treatments for adolescent drug users. PUBLIC HEALTH RELEVANCE: The current study will characterize the effects of marijuana (MJ) on frontolimbic brain functioning in healthy teens. It will also determine whether physical activity or aerobic fitness normalizes the negative consequences of MJ use on brain function. These findings will lead to the development of viable low-cost addiction prevention or ameliorative tools in reducing negative consequences of repeated MJ use during adolescence.